Cellular events during ovine implantation and impact for gestation
Greg A. Johnson, Fuller W. Bazer, Robert C. Burghardt, Guoyao Wu, Heewon Seo, Avery C. Kramer, Bryan A. McLendon
The establishment of pregnancy in sheep includes elongation of the blastocyst into a filamentous conceptus, pregnancy recognition, production of histotroph, attachment of the conceptus to the endometrium for implantation, and development of synepitheliochorial placentation. These processes are complex, and this review describes some of the molecular events that underlie and support successful pregnancy. The free-floating sheep blastocyst elongates into a filamentous conceptus and metabolizes, or is responsive to, molecules supplied by the endometrium as histotroph. Amongst these molecules are SPP1, glucose and fructose, and arginine that stimulate the MTOR nutrient sensing system. The placental trophectoderm of elongating conceptuses initiate pregnancy recognition and implantation. The mononucleate cells of the trophectoderm secrete IFNT, which acts on the endometrial LE to block increases in estrogen receptor α to preclude oxytocin receptor expression, thereby preventing oxytocin from inducing luteolytic pulses of PGF2α. In addition, IFNT increases expression of IFN stimulated genes in the endometrial stroma, including ISG15, a functional ubiquitin homologue. Implantation is the initial step in placentation, and includes sequential pre-contact, apposition, and adhesion phases. Implantation in sheep includes downregulation of Muc1 and interaction of GLYCAM1, galectin 15 (LGALS15) and SPP1 with lectins and integrins (αvβ3). Sheep have synepitheliochorial placentation in which mononucleate trophectoderm cells fuse to form binucleate cells (BNCs). BNCs migrate and fuse with endometrial LE cells to form trinucleate syncytial cells, and these syncytia enlarge through continued BNC fusion to form syncytial plaques that form the interface between endometrial and placental tissues within the placentome. The placentae of sheep organize into placentomal and interplacentomal regions. In placentomes there is extensive interdigitation of endometrial and placental tissues to provide hemotrophic nutrition to the fetus. In interplacentomal regions there is epitheliochorial attachment of endometrial LE to trophectoderm, mediated through focal adhesion assembly, and areolae that take up histotroph secreted by endometrial GE.
Al-Shami R, Sorense, ES, Ek-Rylander B, Andersson G, Carson DD, Farach-Carson MC. 2005. Phosphorylated osteopontin promotes migration of human choriocarcinoma cells via a p70S6 kinase-dependent pathway. J Cell Biochem, 94:1218-1233.
Aplin JD, Meseguer M, Simon C, Ortiz ME, Croxatto H, Jones CJ. 2001. MUC1, glycans and the cell-surface barrier to embryo implantation. Biochem Soc Trans, 29:153-156.
Austin KJ, Bany BM, Belden EL, Rempel LA, Cross JC, Hansen TR. 2004. Interferon-stimulated gene-15 (Isg15) expression is up-regulated in the mouse uterus in response to the implanting conceptus. Endocrinology, 144:3107-3113.
Bazer FW, Johnson GA, Spencer TE. 2005. Growth and development: pre-implantation embryo. In: Pond WG, Bell AW (Ed.). Encyclopedia of Animal Science. New York, NY: Marcel Dekker. Vol. 1, pp 1-3.
Bazer FW, Spencer TE, Thatcher WW. 2011. Growth and development of the ovine conceptus. J Anim Sci, 90:159-170.
Bazer FW, Johnson G A, Song G, Wu G. 2012a. Pregnancy recognition signaling, fetal-placental development and prenatal fetal programming. In: Astiz Blanco S, Bonzalez Buines A (Ed.). Animal Reproduction in Livestock. Oxford, UK: Eolss Publishers. (Encyclopedia of Life Support Systems – Eolss).
Bazer FW, Song G, Kim J, Erikson DW, Johnson GA, Burghardt RC, Gao H, Satterfield MC, Spencer TE, Gao W. 2012b. Mechanistic mammalian target of rapamycin (MTOR) cell signaling: effects of select nutrients and secreted phosphoprotein 1 on development of mammalian conceptuses. Mol Cell Endocrinol, 354:22-33.
Bebington C, Bell SC, Doherty FJ, Fazleabas AT, Fleming SD. 1999a. Localization of ubiquitin and ubiquitin cross-reactive protein in human and baboon endometrium and decidua during the menstrual cycle and early pregnancy. Biol Reprod, 60:920-928.
Bebington C, Doherty FJ, Fleming SD. 1999b. Ubiquitin cross-reactive protein gene expression is increased in decidualized endometrial stromal cells at the initiation of pregnancy. Mol Hum Reprod, 5:966-972.
Bowen JA, Bazer FW, Burghardt RC. 1996. Spatial and temporal analyses of integrin and Muc-1 expression in porcine uterine epithelium and trophectoderm in vivo. Biol Reprod, 55:1098-1106.
Burghardt RC, Johnson GA, Jaeger LA, Ka H, Garlow JE, Spencer TE and Bazer FW. 2002. Integrins and extracellular matrix proteins at the maternal/fetal interface in domestic animals. Cells Tissues Organs, 172:202-217.
Burghardt RC, Burghardt JR, Taylor II JD, Reeder AT, Nguyen BT, Spencer TE, Johnson GA. 2009. Enhanced focal adhesion assembly reflects increased mechanosensation and mechanotransduction along the maternal/conceptus interface during pregnancy in sheep. Reproduction, 137:583-593.
Carson DD, Bagchi I, Dey SK, Enders AC, Fazleabas AT, Lessey BA, Yoshinaga K. 2000. Embryo implantation. Dev Biol, 223:217-237.
Choi Y, Johnson GA, Burghardt RC, Berghman LR, Joyce MM, Taylor KM, Stewart MD, Bazer FW, Spencer TE. 2001. Interferon regulatory factor-two restricts expression of interferon-stimulated genes to the endometrial stroma and glandular epithelium of the ovine uterus. Biol Reprod, 65:1038-1049.
Choi Y, Johnson GA, Spencer TE, Bazer FW. 2003. Pregnancy and interferon tau regulate MHC class I and beta-2-microglobulin expression in the ovine uterus. Biol Reprod, 68:1703-1710.
Denker HW. 1993. Implantation: a cell biological paradox. J Exp Zool, 266:541-558.
Fleming JGW, Spencer TE, Safe SH, Bazer FW. 2005. Estrogen regulates transcription of the ovine oxytocin receptor through GC-rich SP1 promoter elements. Endocrinology, 147:899-911.
Gao H, Wu G, Spencer TE, Johnson GA, Bazer FW. 2009a. Select nutrients in the ovine uterine lumen: VI. Expression of FK506-binding protein 12-rapamycin complex-associated protein 1 (FRAP1) and associated regulators and effectors of mRORC1 and mTORC2 complexes in ovine uteri and peri-implantation conceptuses. Biol Reprod, 81:87-100.
Gao H, Wu G, Spencer TE, Johnson GA, Li X, Bazer FW. 2009b. Select nutrients in the ovine uterine lumen: I. Amino acids, glucose and ions in uterine lumenal fluid of cyclic and pregnant ewes. Biol Reprod, 80:86-93.
Gray CA, Taylor KM, Ramsey WS, Hill J, Bazer FW, Bartol FF, Spencer TE. 2001. Endometrial glands are required for pre_implantation conceptus elongation and survival. Biol Reprod, 64:1608-1613.
Gray CA, Burghardt RC, Johnson GA, Bazer FW, Spencer TE. 2002. Evidence that absence of endometrial gland secretions in uterine glad knockout ewes compromises conceptus survival and elongation. Reproduction, 124:289-300.
Gray CA, Adelson DL, Bazer FW, Burghardt RC, Meeusen EN, Spencer TE. 2004. Discovery and characterization of an epithelial-specific galectin in the endometrium that forms crystals in the trophectoderm. Proc Natl Acad Sci USA, 101:7982-7987.
Guillomot M, Flechon JE, Wintenberger-Torres S. 1981. Conceptus attachment in the ewe: an ultrastructural study. Placenta, 2:169-182.
Haas AL, Aherns P, Bright PM, Amhel H. 1987. Interferon induces a 15-kilodalton protein exhibiting marked homology to ubiquitin. J Biol Chem, 262:11315-11323.
Hansen TR, Pru JL. 2014. ISGylation: a conserved pathway in mammalian pregnancy. Adv Exp Med Biol, 759:13-31.
Hansen TR, Dinedino L, Spencer TE. 2017. Paracrine and endocrine actions of interferon tau (IFNT). Reproduction, 154:F45-F59.
Johnson GA, Austin KJ, Van Kirk EA, Hansen TR. 1998. Pregnancy and interferon-tau induce conjugation of bovine ubiquitin cross-reactive protein to cytosolic uterine proteins. Biol Reprod, 58:898-904.
Johnson GA, Burghardt RC, Spencer TE, Newton GR, Ott TL, Bazer FW. 1999a. Ovine osteopontin II. Osteopontin and alpha(v)beta(3) integrin expression in the uterus and conceptus during the peri-implantation period. Biol Reprod, 61:892-899.
Johnson GA, Spencer TE, Burghardt RC, Bazer FW. 1999b. Ovine osteopontin. I. Cloning and expression of mRNA in the uterus during the peri-implantation period. Biol Reprod, 61:884-891.
Johnson GA, Spencer TE, Hansen TR, Austin KJ, Burghardt RC, Bazer FW. 1999c. Expression of the interferon-tau inducible ubiquitin cross-reactive protein in the ovine uterus. Biol Reprod, 61:312-318.
Johnson GA, Spencer TE, Burghardt RC, Taylor KM, Gray CA and Bazer FW. 2000. Progesterone modulation of osteopontin gene expression in the ovine uterus. Biol Reprod, 62:1315-1321.
Johnson GA, Bazer FW, Jaeger LA, Ka H, Garlow JE, Pfarrer C, Spencer TE, Burghardt RC. 2001. Muc-1, integrin and osteopontin expression during the implantation cascade in sheep. Biol Reprod, 65:820-828.
Johnson GA, Burghardt RC, Bazer FW, Spencer TE. 2003. Minireview: Osteopontin: roles in implantation and placentation. Biol Reprod, 69:1458-1471.
Johnson GA. 2008. Uterine stromal cell differentiation in non-decidualizing species. In: Aplin JD, Fazleabas AT, Glasser SR, Giudice LC (Ed.). The Endometrium: Molecular, Cellular & Clinical Perspectives. 2nd ed. Abingdon, OX, UK: Informa Healthcare. pp. 409-421.
Johnson GA, Bazer FW, Burghardt RC, Spencer TE, Wu G, Bayless KJ. 2009. Conceptus-uterus interactions in pigs: endometrial gene expression in response to estrogens and interferons from conceptuses. Soc Reprod Fertil Suppl, 66:321-332.
Johnson GA, Burghardt RC and Bazer FW. 2014. Osteopontin: a leading candidate adhesion molecule for implantation in pigs and sheep. J Anim Sci Biotechnol, 5:56-70.
Joyce MM, White FJ, Burghardt RC, Muñiz JJ, Spencer TE, Bazer FW, Johnson GA. 2005. Interferon stimulated gene 15 (ISG15) conjugates to cytosolic proteins and is expressed at the uterine-placental interface throughout ovine pregnancy. Endocrinology, 146:675-684.
Joyce MM, Burghardt JR, Burghardt RC, Hooper RN, Bazer FW, Johnson GA. 2008. Uterine major histocompatibility class I molecules and beta 2 microglobulin are regulated by progesterone and conceptus interferons during pig pregnancy. J Immunol, 181:2494-2505.
Kim J, Erikson DW, Burghardt RC, Spencer TE, Wu G, Bayless KJ, Johnson GA, Bazer FW. 2010. Secreted phosphoprotein 1 binds integrins to initiate multiple cell signaling pathways, including FRAP1/mTOR, to support attachment and force-generated migration of trophectoderm cells. Matrix Biol, 29:369-382.
Kim J, Burghardt RC, Wu G, Johnson GA, Spencer TE, Bazer FW. 2011a. Select Nutrients in the ovine uterine lumen: VII. Effects of arginine, leucine, glutamine and glucose on trophectodem cell signaling, proliferation and migration. Biol Reprod, 84:70-78.
Kim J, Burghardt RC, Wu G, Johnson GA, Spencer TE, Bazer FW. 2011b. Select Nutrients in the ovine uterine lumen: VIII. Arginine stimulates proliferation of ovine trophectoderm cells through mTOR RPS6K RPS6 signaling cascade and synthesis of nitric oxide and polyamines. Biol Reprod, 84:62-69.
Kim J, Burghardt R, Wu G, Johnson GA, Spencer TE, Bazer FW. 2011c. Select Nutrients in the ovine uterine lumen: IX. Differential effects of arginine, leucine, glutamine and glucose on interferon tau, orinithine decarboxylase and nitric oxide synthase in the ovine conceptus. Biol Reprod, 84:1139-1147.
Kim J, Song G, Wu G, Bazer FW. 2012. Functional roles of fructose. Proc Natl Acad Sci USA, 109:E1619-1628.
Kimber SJ, Illingworth IM, Glasser SR. 1995. Expression of carbohydrate antigens in the rat uterus during early pregnancy and after ovariectomy and steroid replacement. J Reprod Fertil, 103:75-87.
Lessey BA. 2002. Adhesion molecules and implantation. J Reprod Immunol, 55:101-112.
Liu L, Chen L, Chung L, Huang S. 2008. Rapamycin inhibits F-actin reorganization and phosphorylation of focal adhesion proteins. Oncogene, 27:4998-5010.
Martin PM, Sutherland AE. 2001. Exogenous amino acids regulate trophectoderm differentiation in the mouse blastocyst through an mTOR-dependent pathway. Develop Biol 240:182-193.
Muñiz JJ, Joyce MM, Taylor JD, Burghardt JR, Burghardt RC, Johnson GA. 2006. Glycosylation dependent cell adhesion molecule 1 (GlyCAM-1)-like protein and L-selectin expression in sheep interplacentomal and placentomal endometrium. Reproduction, 131:751-761.
Nielsen FC, Ostergaard L, Nielsen J, Christiansen J. 1995. Growth-dependent translation of IGF-II mRNA by a rapamycin-sensitive pathway. Nature, 377:358-362.
Roberts RM, Smith GW, Bazer FW, Cibelli J, Seidel GE Jr, Bauman DE, Reynolds LP, Ireland JJ. 2009. Research priorities. Farm animal research in crisis. Science, 324:468-469.
Szafranska B, Wie S, Green J, Roberts RM. 1995. Porcine pregnancy-associated glycoproteins: new members of the aspartic proteinase gene family expressed in trophectoderm. Biol Reprod, 53:21-28.
Senger DR, Perruzzi CA. 1996. Cell migration promoted by a potent GRGDS-containing thrombin-cleavage fragment of OPN. Biochim Biophys Acta, 1314:13-24.
Shiflett J, Purcell W, Marsch D, Rogers P. 2007. Analysis of lamb demand in the United States. In: American Lamb Board Report. Available on: http://www.lambcheckoff. com/wp-content/uploads/ 2012/04/juniper-2007.pdf. Accessed on: Nov 9, 2016.
Spencer TE, Bartol FF, Bazer FW, Johnson GA, Joyce MM. 1999. Identification and characterization of glycosylation-dependent cell adhesion molecule 1-like protein expression in the ovine uterus. Biol Reprod, 60:241-250.
Spencer TE, Burghardt RC, Johnson GA, Bazer FW. 2004a. Conceptus signals for establishment and maintenance of pregnancy. Anim Reprod Sci, 82/83:537-550.
Spencer TE, Johnson GA, Bazer FW, Burghardt, RC. 2004b. Implantation mechanisms: insights from the sheep. Reproduction, 128:656-668.
Spencer TE, Johnson GA, Bazer FW, Burghardt RC. 2007. Fetal-maternal interactions during the establishment of pregnancy in ruminants. Soc Reprod Fertil Suppl, 64 379-396.
Taniguchi T, Ogasawara K, Takaoka A, Tanaka N. 2001. IRF family of transcription factors as regulators of host defense. Annu Rev Immunol, 19:623-655.
Wang X, Johnson GA, Burghardt RC, Wu G, Bazer FW. 2016a. Uterine histotroph and conceptus development. II. arginine and secreted phosphoprotein 1 cooperatively stimulate migration and adhesion of ovine trophectoderm cells via focal adhesion-MTORC2 mediated cytoskeleton reorganization. Biol Reprod, 95:71-83.
Wang X, Li D, Wu G, Bazer FW. 2016b. Functional roles of fructose: crosstalk between O-linked glycosylation and phosphorylation of Akt-TSC2-MTOR cell signaling cascade. Biol Reprod, 95:102-119.
Wilkinson KD. 2000. Ubiquitination and deubiquitination: targeting of proteins for degradation by the proteasome. Cell Develop Biol, 11:141-148.
Wooding FB. 1984. Role of binucleate cells in fetomaternal cell fusion at implantation in the sheep. Am J Anat, 170:233-250.
Wooding FB, Burton GJ. 2008. Synepitheliochorial placentation: ruminants (ewe and cow). In: Wooding FB, Burton GJ. Comparative Placentation: Structure, Function and Evolution. Heidelberg: Springer-Verlag. Pp. 133-144.
Wu G, Bazer FW, Satterfield MC, Li XL, Wang XQ, Johnson GA, Burghardt RC, Dai ZL, Wang JJ, Wu ZL. 2013. Impacts of arginine nutrition on embryonic and fetal development in mammals. Amino Acids, 45:241-256.
Wu G, Bazer FW, Johnson GA, Herring C, Seo H, Dai ZL, Wang JJ, Wu ZL, Wang XL. 2017. Functional amino acids in the development of the pig placenta. Mol Reprod Dev, 84:879-882.